Journal
JAMA ONCOLOGY
Volume 6, Issue 5, Pages 724-734Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jamaoncol.2020.0197
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Categories
Funding
- intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- National Institutes of Health [U01CA122371]
- Cancer Center Support [CA21765]
- National Cancer Institute [CA55727]
- Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, La Fundacion La Caixa-Caja Navarra [PI13/01476]
- Spanish Association Against Cance [RTICC RD 12/0036/0066]
- Foundation for Applied Medical Research
- Cancer Research Thematic Network of the Instituto de Salud Carlos III
- Centro de Investigacion Biomedica en Red de Cancer [CB16/12/00443, CB16/12/00350]
- Spanish Ministry of Economy and Competitiveness [RTI2018-094507-B-100]
- National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust
- University College London
- University College London Experimental Cancer Centre
- 2013 Hyundai Hope on Wheels (University of Minnesota)
- National Cancer Institute, National Institutes of Health (Children's Oncology Group) [U10 CA98543, U24 CA114766]
- QuadW Foundation (Children's Oncology Group)
- Regione Emilia-Romagna
- Royal National Orthopaedic Hospital Musculoskeletal Research Programme
- Biobank
- Australian National Health and Medical Research Council [APP1004017]
- Cancer Australia [APP1067094]
- Zach Sobiech Osteosarcoma Fund at the Children's Cancer Research Fund
- American Lebanese-Syrian Associated Charities
- Departamento De Salud, Gobierno De Navarra, Proyectos de Biomedicina 2018
- Bone Cancer Research Trust
- Rainbows for Kate Foundation
- Liddy Shriver Sarcoma Initiative
- Victorian Cancer Agency (International Sarcoma Kindred study)
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Importance Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear. Objective To investigate the germline genetic architecture of 1244 patients with osteosarcoma. Design, Setting, and Participants Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019. Main Outcomes and Measures The frequency of rare pathogenic or likely pathogenic genetic variants. Results Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 x 10(-18)). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53. Conclusions and Relevance In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.
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